GATA4 as a Modulator of Aortic Root Sensitivity to Mechanochemical Disruptions Caused by an Aneurysm-causing Mutation

项目摘要 主动脉瘤是局部扩张，使血管易于夹层或破裂，这两者都是常见的。 与高死亡率有关。Loeys-Dietz综合征（LDS）是一种遗传性动脉瘤疾病， 这些突变损害但不完全破坏TGF-β信号传导。LDS患者有强烈的倾向， 尽管在这种情况下突变的基因普遍表达， 遍布整个脉管系统。造成这种局部脆弱性的机制尚不清楚。在这 建议，我将测试的假设，内在因素表达的平滑肌细胞存在于 主动脉根部使它们更容易受到由以下引起的主动脉机械化学破坏 LDS突变。具体来说，我将研究Gata 4在血管平滑肌细胞亚群中的内在表达， 肌肉细胞引发这些细胞上调GATA 4时，稳态抑制机制，依赖于 这些细胞和细胞外基质之间的适当接触失败。我将得到我的赞助商，博士。 MacFarlane和共同赞助人Dietz博士，以完成以下目标。在目标1中，我将揭示LDS如何 突变影响主动脉细胞外基质结构和局灶性粘连下游的信号传导， 药物干预这些通路对动脉瘤发病机制的影响。在目标2中，我将 通过检测出生后的影响，阐明GATA 4在主动脉根部动脉瘤发病中的作用， Gata 4平滑肌特异性缺失对主动脉根部扩张的影响。在我的同事的帮助下，博士。 Kagohara是空间转录组学的专家，我也将学习使用这种尖端技术， 相关的计算工具来绘制沿着主动脉长度的转录异质性的梯度。我 我将进一步发展我作为独立研究人员的技能，并提高我在心血管领域的专业知识 通过完成重点课程，定期参加科学会议并在会议上发表演讲来学习生物学。到 为了提高我在科学交流方面的技能，我将寻求更多的指导和教学机会， 包括在约翰霍普金斯大学教授本科生遗传学课程。通过完成这个 根据我的建议，我将获得必要的经验和技能，以获得博士后研究员的职位， 最终在心血管研究领域建立独立的学术生涯。

PROJECT SUMMARY Aortic aneurysms are localized dilations that predispose the vessel to dissection or rupture, both of which are associated with high mortality. Loeys-Dietz Syndrome (LDS) is a hereditary aneurysm disorder caused by mutations that impair, but do not fully disrupt, TGF-β signaling. LDS patients have a strong predisposition for disease in the aortic root even though the genes that are mutated in this condition are ubiquitously expressed throughout the vasculature. The mechanisms that underlie this localized vulnerability remain unclear. In this proposal, I will test the hypothesis that intrinsic factors expressed in smooth muscle cells present in the aortic root render them more susceptible to the mechanochemical disruptions of the aorta caused by LDS mutations. Specifically, I will investigate if intrinsic expression of Gata4 in a subset of vascular smooth muscle cells primes these cells to upregulate GATA4 when homeostatic inhibitory mechanisms that depend on proper contacts between these cells and the extracellular matrix fail. I will be supported by my sponsor, Dr. MacFarlane, and co-sponsor, Dr. Dietz, to complete the following aims. In Aim 1, I will uncover how LDS mutations affect aortic extracellular matrix structure and signaling downstream of focal adhesions and examine the effect of pharmacological interference with these pathways on aneurysm pathogenesis. In Aim 2, I will clarify the role of GATA4 in the pathogenesis of aortic root aneurysm by examining the effect of postnatal smooth muscle specific deletion of Gata4 on aortic root dilation. With the help of my collaborator, Dr. Kagohara, who is an expert in spatial transcriptomics, I will also learn use this cutting-edge technology and related computational tools to map the gradient of transcriptional heterogeneity along the length of the aorta. I will further develop my skills as an independent researcher and enhance my expertise in cardiovascular biology by completing focused coursework and regularly attending and presenting at scientific conferences. To improve my skills in scientific communication, I will seek out additional mentoring and teaching opportunities, including teaching an undergraduate genetics course at Johns Hopkins University. By completing this proposal, I will acquire the experience and skills necessary to attain a position as a postdoctoral fellow, and ultimately establish an independent academic career in cardiovascular research.